Interstitial diphtheria toxin-epidermal growth factor fusion protein therapy produces regressions of subcutaneous human glioblastoma multiforme tumors in athymic nude mice

Tie Fu Liu, Philip D. Hall, Kimberley A. Cohen, Mark C. Willingham, Jiaozhong Cai, Andrew Thorburn, Arthur E. Frankel

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Purpose: The novel fusion protein, DAB389EGF, composed of the catalytic and translocation domains of diphtheria toxin (DAB389) fused with a His-Ala linker to human epidermal growth factor (EGF) was tested for antiglioma efficacy in an in vivo model of human glioma. Experimental Design: Female athymic nude mice (ages 4-6 weeks) were inoculated s.c. with 10 million U87MG human glioma cells in the right flank. When tumor volumes reached ∼100 mm3 (∼6-8 days), i.t. injections of saline, DAB 389IL2, or DAB389EGF 1, 3, 5 or 10 μg in 50 μL were given every other day for three to six doses. Animals were monitored twice daily and tumor measurements were made by calipers. Results: The maximal tolerated dose (MTD) of DAB389EGF was 3 μg every other day. Above the MTD, animals experienced loss of activity, reduced oral intake, and dehydration. Blood chemistries confirmed elevated blood urea nitrogen, creatinine, aspartate transaminase, and alanine transaminase. Histopathology revealed renal tubular necrosis. At the MTD, tumor regression was seen in all animals. Relapses occurred in 4 of 16 (25%) of animals after 1 month. These tumors contained EGF receptor, were sensitive in vitro to DAB389EGF, and responded to a second course of i.t. DAB389EGF. Conclusions: DAB389EGF fusion protein shows in vivo antiglioma efficacy in a s.c. tumor model and warrants further preclinical testing in an i.e. tumor model for eventual treatment of patients with recurrent or refractory EGF receptor-positive glioblastoma multiforme.

Original languageEnglish (US)
Pages (from-to)329-334
Number of pages6
JournalClinical Cancer Research
Volume11
Issue number1
StatePublished - Jan 1 2005

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Diphtheria Toxin
Glioblastoma
Epidermal Growth Factor
Nude Mice
Maximum Tolerated Dose
Neoplasms
Proteins
histidinoalanine
Epidermal Growth Factor Receptor
Glioma
Therapeutics
Blood Urea Nitrogen
Aspartate Aminotransferases
Tumor Burden
Alanine Transaminase
Dehydration
Catalytic Domain
Creatinine
Research Design
Necrosis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Interstitial diphtheria toxin-epidermal growth factor fusion protein therapy produces regressions of subcutaneous human glioblastoma multiforme tumors in athymic nude mice. / Liu, Tie Fu; Hall, Philip D.; Cohen, Kimberley A.; Willingham, Mark C.; Cai, Jiaozhong; Thorburn, Andrew; Frankel, Arthur E.

In: Clinical Cancer Research, Vol. 11, No. 1, 01.01.2005, p. 329-334.

Research output: Contribution to journalArticle

Liu, Tie Fu ; Hall, Philip D. ; Cohen, Kimberley A. ; Willingham, Mark C. ; Cai, Jiaozhong ; Thorburn, Andrew ; Frankel, Arthur E. / Interstitial diphtheria toxin-epidermal growth factor fusion protein therapy produces regressions of subcutaneous human glioblastoma multiforme tumors in athymic nude mice. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 1. pp. 329-334.
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abstract = "Purpose: The novel fusion protein, DAB389EGF, composed of the catalytic and translocation domains of diphtheria toxin (DAB389) fused with a His-Ala linker to human epidermal growth factor (EGF) was tested for antiglioma efficacy in an in vivo model of human glioma. Experimental Design: Female athymic nude mice (ages 4-6 weeks) were inoculated s.c. with 10 million U87MG human glioma cells in the right flank. When tumor volumes reached ∼100 mm3 (∼6-8 days), i.t. injections of saline, DAB 389IL2, or DAB389EGF 1, 3, 5 or 10 μg in 50 μL were given every other day for three to six doses. Animals were monitored twice daily and tumor measurements were made by calipers. Results: The maximal tolerated dose (MTD) of DAB389EGF was 3 μg every other day. Above the MTD, animals experienced loss of activity, reduced oral intake, and dehydration. Blood chemistries confirmed elevated blood urea nitrogen, creatinine, aspartate transaminase, and alanine transaminase. Histopathology revealed renal tubular necrosis. At the MTD, tumor regression was seen in all animals. Relapses occurred in 4 of 16 (25{\%}) of animals after 1 month. These tumors contained EGF receptor, were sensitive in vitro to DAB389EGF, and responded to a second course of i.t. DAB389EGF. Conclusions: DAB389EGF fusion protein shows in vivo antiglioma efficacy in a s.c. tumor model and warrants further preclinical testing in an i.e. tumor model for eventual treatment of patients with recurrent or refractory EGF receptor-positive glioblastoma multiforme.",
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